Abstract TP27: Transcriptional and Functional Characterization of Microglia in Vascular Dementia

Introduction: Proper function of the brain relies on sufficient blood supply to meet local energy demand. Age-related pathologies like cerebral small vessel disease (cSVD) compromise the ability of blood vessels to meet local energy demands and lead, over time, to the development of vascular dementia (VaD). Microglia are essential for maintaining homeostasis and have been shown to exacerbate inflammation and disease progression in neurodegenerative diseases. Activated microglia are present in the white matter lesions of human post-mortem VaD brains. However, their role in VaD progression is poorly understood. Hypothesis: Our main objective is to identify microglial pathways that contribute to VaD. We hypothesize microglial dysregulation interferes with brain homeostasis and wound healing, ultimately contributing to disease progression. Methods: Post-mortem samples of periventricular white matter from male and female elderly individuals exhibiting brain pathology consistent with VaD (n=4), along with age- and sex-matched controls without VaD (n=4) were acquired from the NIH NeuroBioBank. We performed single-nuclei RNA sequencing followed by differential gene expression analysis using Seurat and downstream analyses using Ingenuity Pathway Analysis. Results: Over 30,000 nuclei were analyzed. Transcriptomic results reveal profound differences in the microglial transcriptome in VaD, with 690 differentially regulated genes in microglia between cases and controls. Genes related to pathways such as complement production, phagocytosis, macrophage activation and overall protein production are downregulated in VaD while IL-10 production is upregulated (Figure 1B). Conclusions: Our data suggests microglia in VaD adopt a unique transcriptional signature, distinct from that observed in disease-associated microglia in other neurodegenerative conditions, which may impact their ability to maintain homeostasis in VaD.